Lutzomyia longipalpis salivary proteins elicit human innate and adaptive immune responses detrimental to Leishmania parasites

Leishmania parasites are transmitted via the bite of infected sand flies, whose saliva modulates host immune responses to promote Leishmania infection, especially in unexposed individuals. For humans in endemic areas, the immune consequences of chronic exposure to sand fly saliva remain poorly understood. We performed a human challenge study with Lutzomyia longipalpis , the primary vector of visceral leishmaniasis in the Americas. Fifteen healthy volunteers were exposed multiple times to uninfected Lu. longipalpis bites over the course of a year. PBMCs collected after several exposures were stimulated ex vivo by recombinant Lu. longipalpis salivary proteins to measure cytokine responses. Two salivary proteins, LJM19 and LJL143, elicited T _H 1-polarized cytokine responses, but with high co-expression of the T _H 2 cytokine IL-13. LJM19 also induced higher levels of IL-6 and IL-7, while both LJM19 and LJL143 induced the innate cytokines IL-1β and IFN-α. Importantly, T _H 1 polarization induced by LJM19 or LJL143 in PBMCs correlated with enhanced killing of Leishmania in co-cultured macrophages. Skin biopsies from two volunteers revealed bite site infiltration with CD4 ^- CD8 ^- T cells. Our data suggest that sand fly exposed individuals demonstrate robust innate and adaptive cellular immune responses to vector salivary proteins that can be co-opted to protect humans against Leishmania infection.